Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection.

Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (COVID-19) pandemic. Here we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy.

Safety and Immunogenicity of an mRNA-1273 Booster in Children.

BACKGROUND: A 2-dose mRNA-1273 primary series in children aged 6 months-5 years (25-µg) and 6-11 years (50-µg) had an acceptable safety profile and was immunogenic in the phase 2/3 KidCOVE study. We present data from KidCOVE participants who received an mRNA-1273 booster dose. METHODS: An mRNA-1273 booster dose (10-µg for children aged 6 months-5 years; 25-µg for children aged 6-11 years; age groups based on participant age at enrollment) was administered ≥6 months after primary series completion. The primary safety objective was the safety and reactogenicity of an mRNA-1273 booster dose. The primary immunogenicity objective was to infer efficacy of an mRNA-1273 booster dose by establishing noninferiority of neutralizing antibody (nAb) responses after a booster in children compared with nAb responses observed after the mRNA-1273 primary series in young adults (18-25 years) from the pivotal efficacy study. Data were collected from March 2022 to June 2023. RESULTS: Overall, 153 (6 months-5 years) and 2519 (6-11 years) participants received an mRNA-1273 booster dose (median age at receipt of booster: 2 and 10 years, respectively). The booster dose safety profile was generally consistent with that of the primary series in children; no new safety concerns were identified. An mRNA-1273 booster dose elicited robust nAb responses against ancestral SARS-CoV-2 among children and met prespecified noninferiority success criteria when compared with responses observed after the primary series in young adults. CONCLUSIONS: Safety and immunogenicity data support administration of a mRNA-1273 booster dose in children aged 6 months to 11 years. CLINICAL TRIALS REGISTRATION: NCT04796896.

Revolutionizing cancer treatment in India: Evaluating the unmet need, economics, and a roadmap for project implementation of particle therapy.

INTRODUCTION: This study aims to quantitatively assess eligible patients and project the demand for particle therapy facilities in India from 2020 to 2040. In addition, an economic analysis evaluates the financial feasibility of implementing this technology. The study also examines the prospective benefits and challenges of adopting this technology in India. METHODOLOGY: Cancer incidence and projected trends were analyzed for pediatric patients using the Global Childhood Cancer microsimulation model and adult patients using the Globocan data. Economic cost evaluation is performed for large-scale combined particle (carbon and proton-three room fixed-beam), large-scale proton (one gantry and two fixed-beam), and small-scale proton (one gantry) facility. RESULTS: By 2040, the estimated number of eligible patients for particle therapy is projected to reach 161,000, including approximately 14,000 pediatric cases. The demand for particle therapy facilities is projected to rise from 81 to 97 in 2020 to 121 to 146 by 2040. The capital expenditure is estimated to be only 3.7 times that of a standard photon linear accelerator over a 30-year period. Notably, the treatment cost can be reduced to USD 400 to 800 per fraction, substantially lower than that in high-income countries (USD 1000 to 3000 per fraction). CONCLUSION: This study indicates that, in the Indian scenario, all particle therapy models are cost-beneficial and feasible, with large-scale proton therapy being the most suitable. Despite challenges such as limited resources, space, a skilled workforce, referral systems, and patient affordability, it offers substantial benefits. These include the potential to treat many patients and convenient construction and operational costs. An iterative phased implementation strategy can effectively overcome these challenges, paving the way for the successful adoption of particle therapy in India. PLAIN LANGUAGE SUMMARY: In India, the number of eligible patients benefiting from high-precision particle therapy technology is projected to rise till 2040. Despite high upfront costs, our study finds the long-term feasibility of all particle therapy models, potentially offering a substantial reduction in treatment cost compared to high-income countries. Despite challenges, India can succeed with an iterative phased approach.

Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab.

BACKGROUND: Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease. METHODS: In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization. RESULTS: In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P = 0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively). CONCLUSIONS: Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060.).

Pathological findings associated with the updated European Society of Cardiology 2022 guidelines for preoperative cardiac testing: an observational cohort modelling study.

BACKGROUND: In 2022, the European Society of Cardiology updated guidelines for preoperative evaluation. The aims of this study were to quantify: (1) the impact of the updated recommendations on the yield of pathological findings compared with the previous guidelines published in 2014; (2) the impact of preoperative B-type natriuretic peptide (NT-proBNP) use for risk estimation on the yield of pathological findings; and (3) the association between 2022 guideline adherence and outcomes. METHODS: This was a secondary analysis of MET-REPAIR, an international, prospective observational cohort study (NCT03016936). Primary endpoints were reduced ejection fraction (EF<40%), stress-induced ischaemia, and major adverse cardiovascular events (MACE). The explanatory variables were class of recommendations for transthoracic echocardiography (TTE), stress imaging, and guideline adherence. We conducted second-order Monte Carlo simulations and multivariable regression. RESULTS: In total, 15,529 patients (39% female, median age 72 [inter-quartile range: 67-78] yr) were included. The 2022 update changed the recommendation for preoperative TTE in 39.7% patients, and for preoperative stress imaging in 12.9% patients. The update resulted in missing 1 EF <40% every 3 fewer conducted TTE, and in 4 additional stress imaging per 1 additionally detected ischaemia events. For cardiac stress testing, four more investigations were performed for every 1 additionally detected ischaemia episodes. Use of NT-proBNP did not improve the yield of pathological findings. Multivariable regression analysis failed to find an association between adherence to the updated guidelines and MACE. CONCLUSIONS: The 2022 update for preoperative cardiac testing resulted in a relevant increase in tests receiving a stronger recommendation. The updated recommendations for TTE did not improve the yield of pathological cardiac testing.

Factors affecting adherence to recommendations on pre-operative cardiac testing: A cohort study.

BACKGROUND: Cardiac risk evaluation prior to noncardiac surgery is fundamental to tailor peri-operative management to patient's estimated risk. Data on the degree of adherence to guidelines in patients at cardiovascular risk in Europe and factors influencing adherence are underexplored. OBJECTIVES: The aim of this analysis was to describe the degree of adherence to [2014 European Society of Cardiology (ESC)/European Society of Anaesthesiology (ESA) guidelines] recommendations on rest echocardiography [transthoracic echocardiography (TTE)] and to stress imaging prior to noncardiac surgery in a large European sample and to assess factors potentially affecting adherence. DESIGN: Secondary analysis of a multicentre, international, prospective cohort study (MET-REPAIR). SETTING: Twenty-five European centres of all levels of care that enrolled patients between 2017 and 2020. PATIENTS: With elevated cardiovascular risk undergoing in-hospital elective, noncardiac surgery. MAIN OUTCOME MEASURES: (Non)adherence to each pre-operative TTE and stress imaging recommendations classified as guideline-adherent, overuse and underuse. We performed descriptive analysis. To explore the impact of patients' sex, age, geographical region, and hospital teaching status, we conducted multivariate multinominal regression analysis. RESULTS: Out of 15 983 patients, 15 529 were analysed (61% men, mean age 72 ±â€Š8 years). Overuse (conduction in spite of class III) and underuse (nonconduction in spite of class I recommendation) for pre-operative TTE amounted to 16.6% (2542/15 344) and 6.6% (1015/15 344), respectively. Stress imaging overuse and underuse amounted to 1.7% (241/14 202) and 0.4% (52/14 202) respectively. Male sex, some age categories and some geographical regions were significantly associated with TTE overuse. Male sex and some regions were also associated with TTE underuse. Age and regions were associated with overuse of stress imaging. Male sex, age, and some regions were associated with stress imaging underuse. CONCLUSION: Adherence to pre-operative stress imaging recommendation was high. In contrast, adherence to TTE recommendations was moderate. Both patients' and geographical factors affected adherence to joint ESC/ESA guidelines. TRIAL REGISTRATION: NCT03016936.

Is an all-phase ITV (internal target volume) a gold standard in the target definition of hepatocellular carcinoma?

BACKGROUND: Stereotactic ablative body radiation (SABR) is a well-recognized treatment option for hepatocellular carcinoma (HCC). Due to the inherent motion of liver tumors, effective motion management is crucial for successful SABR. In the motion-encompassing motion management technique, all 10 respiratory phase image datasets are delineated and designated as the internal target volume (ITV). Some treatment centers use single or combination image sets to delineate the target volume. This study determines which specialty image set most closely matches an all-phase ITV contour on a synchronized contrast-enhanced 4DCT. MATERIALS AND METHODS: Synchronized 4DCT contrast and delayed scans were acquired for 10 patients in the study. The maximum intensity projection (MiP), average intensity projection (AvgIP), and minimum intensity projection (MinIP) images were generated. The ITV delineation was done in all 10 phases (ITV_all_phase). The ITV_2phase combines the peak inhale and exhale phase, ITV_2 M combines MiP and MinIP, and ITV_3 M combines MiP, MinIP, and AvgIP. All ITVs were compared to ITV_all_phase with Dice similarity index (DSI) and volumes. RESULTS: Using ITV_all_phase as the reference, the DSI and the mean ITV volumes for the different ITVs were as follows: ITV_all_phase (1 and 116.69 cc), ITV_2phase (0.87 and 105.27 cc), MiP (0.76 and 98.24 cc), AvgIP (0.72 and 94.54 cc), ITV_MinIP (0.67 and 81.08 cc), ITV_2 M (0.84 and 106.26 cc), and ITV_3 M (0.86 and 112.51 cc). CONCLUSION: The study demonstrates that in the motion-encompassing technique of motion management, the target volume generated by delineating all phases of 4DCT provides the most accurate representation for patients with HCC. Specialty image sets and their combinations, while sometimes close, tend to result in less accurate targeting. Hence, the all-phase 4DCT method should be preferred to avoid geographical misses and ensure optimal treatment outcomes. However, our conclusion may be limited by the technique we employed.

RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial.

Importance: Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. Objective: To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. Design, Setting, and Participants: This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Interventions: Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. Main Outcomes and Measures: The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Results: Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. Conclusions and Relevance: In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. Trial Registration: ClinicalTrials.gov Identifier: NCT04936035.

Efficacy of Triglyceride Glucose Index-Neck Circumference and Triglyceride Glucose Index-Neck-to-Height Ratio in the Diagnosis of Cardiovascular Diseases and Metabolic Syndrome.

BACKGROUND: A group of characteristics known as metabolic syndrome raises the chance of developing diabetes and cardiovascular disease. Insulin resistance (IR) and obesity are regarded as critical metabolic syndrome pathophysiology. OBJECTIVES: The diagnostic accuracy of IR indicators, triglyceride (TG) glucose index-neck circumference (TyG-NC), and TG glucose index-neck-to-height ratio (TyG-NHtR) to be evaluated for the detection of cardiovascular diseases and metabolic syndrome in nondiabetic individuals. MATERIALS AND METHODS: A cross-sectional study was conducted and passed by the Ethics Committee of the institute. The age should be 18 years or older, and subjects should not have diabetes. Each patient's clinical information was gathered, and lab tests were run. The study was done for a period of 1 year. RESULTS: The study has 100 participants. Around 74% of the group was women. Only 26.5% of the group had an obesity diagnosis. Poor fasting plasma glucose levels were found in 19.4% of the research team. Receiver operating characteristic (ROC)-area under the curve (AUC) testing revealed that all examined IR indices can differentiate individuals with metabolic syndrome from those who are healthy. Our analysis laid out the soaring high area under the ROC curve for TyG index and the low stunted area under the ROC curve for TyG-NC. For obesity, all indices showed appreciable diagnostic efficacy, indicating the maximum achieved area under the ROC curve for TyG index and the minimum recorded metabolic score for IR. The AUC in the case of the metabolic score for IR (METS-IR) male sample population was found to be not statistically compelling. CONCLUSION: The exploration of indirect indices, the proposed ones, namely TyG-NC and TyG-NHtR, emphasized an intricate link between cardiovascular diseases and metabolic syndrome.

Synthesis of 6-alkoxy and 6-hydroxy-alkyl amine derivatives of braylin as vasorelaxing agents.

Braylin (10b) is a 8,8-dimethyl chromenocoumarin present in the plants of the family Rutaceae and Meliaceae and possesses vasorelaxing and anti-inflammatory activities. In this study, six 6-alkoxy (10b, 15-19), and twelve 6-hydroxy-alkyl amine (20a-20l) derivatives of braylin (11 and 12) were synthesized to delineate its structural requirement for vasorelaxing activity. The synthesized compounds were evaluated for vasorelaxation response in preconstricted intact rat Main Mesenteric Artery (MMA). The compounds showed l-type VDCC channel blockade depended and endothelium-independent vasorelaxation within the range of Emax < 50.00-96.70 % at 30 µM. Amongst all, 6-alkoxy derivatives were more active than 6-hydroxy-alkyl amine derivatives. The structural refinements about braylin showed that deletion of its methoxy group or homologation beyond ethoxy group presented deleterious effect on vasorelaxation response of braylin. Interestingly, substituting the ethoxy group in 10b presented the best activity and selectivity towards l-type VDCC channel blockade, a specific target cardiovascular function.

Risk assessment for major adverse cardiovascular events after noncardiac surgery using self-reported functional capacity: international prospective cohort study.

BACKGROUND: Guidelines endorse self-reported functional capacity for preoperative cardiovascular assessment, although evidence for its predictive value is inconsistent. We hypothesised that self-reported effort tolerance improves prediction of major adverse cardiovascular events (MACEs) after noncardiac surgery. METHODS: This is an international prospective cohort study (June 2017 to April 2020) in patients undergoing elective noncardiac surgery at elevated cardiovascular risk. Exposures were (i) questionnaire-estimated effort tolerance in metabolic equivalents (METs), (ii) number of floors climbed without resting, (iii) self-perceived cardiopulmonary fitness compared with peers, and (iv) level of regularly performed physical activity. The primary endpoint was in-hospital MACE consisting of cardiovascular mortality, non-fatal cardiac arrest, acute myocardial infarction, stroke, and congestive heart failure requiring transfer to a higher unit of care or resulting in a prolongation of stay on ICU/intermediate care (≥24 h). Mixed-effects logistic regression models were calculated. RESULTS: In this study, 274 (1.8%) of 15 406 patients experienced MACE. Loss of follow-up was 2%. All self-reported functional capacity measures were independently associated with MACE but did not improve discrimination (area under the curve of receiver operating characteristic [ROC AUC]) over an internal clinical risk model (ROC AUCbaseline 0.74 [0.71-0.77], ROC AUCbaseline+4METs 0.74 [0.71-0.77], ROC AUCbaseline+floors climbed 0.75 [0.71-0.78], AUCbaseline+fitnessvspeers 0.74 [0.71-0.77], and AUCbaseline+physical activity 0.75 [0.72-0.78]). CONCLUSIONS: Assessment of self-reported functional capacity expressed in METs or using the other measures assessed here did not improve prognostic accuracy compared with clinical risk factors. Caution is needed in the use of self-reported functional capacity to guide clinical decisions resulting from risk assessment in patients undergoing noncardiac surgery. CLINICAL TRIAL REGISTRATION: NCT03016936.

A comparison of the quality of images of chest X-ray between handheld portable digital X-ray & routinely used digital X-ray machine.

Background & objectives: Chest X-ray (CXR) is an important screening tool for pulmonary tuberculosis (TB). Accessibility to CXR facilities in difficult-to-reach and underserved populations is a challenge. This can potentially be overcome by deploying digital X-ray machines that are portable. However, these portable X-ray machines need to be validated before their deployment in the field. Here, we compare the image quality of CXR taken by a newly developed handheld X-ray machine with routinely used reference digital X-ray machine through the conduct of a feasibility study. Methods: A total of 100 participants with suspected pulmonary TB were recruited from the outpatient departments of a medical college and a community health centre in Agra. Each participant underwent CXR twice, once with each machine. Both sets of de-identified images were independently read by two radiologists, who were blinded to the type of X-ray machine used. The primary outcome was agreement between image qualities produced by these two machines. Results: The intra-observer (radiologist) agreements regarding the status of the 15 CXR parameters ranged between 74 per cent and 100 per cent, with an unweighted mean of 87.2 per cent (95% confidence interval: 71.5-100). The median Cohen's kappa values for intra-observer agreement were 0.62 and 0.67 for radiologists 1 and 2, respectively. In addition, on comparison of the overall median score of quality of the image, the handheld machine images had a higher score for image quality. Interpretation & conclusions: The current study shows that a handheld X-ray machine, which is easy to use and can potentially be carried to any area, produces X-ray images with quality that is comparable to digital X-ray machines routinely used in health facilities.

Assessment of Genetic Diversity, Micromorphology and Antimicrobial Activity in Nepeta cataria L.

The mosquito repellent Nepetalactone rich Nepeta cataria L. (catmint) plant has a variety of therapeutic and industrial potential. Reports on the genetic diversity of N. cataria germplasm are minimal globally and need attention for adding a new variety into commercial cultivation. The present study, therefore, assessed the genetic diversity among thirteen half-sib genotypes of N. cataria using agro economic and phytochemical traits. The experimental set has shown substantial variation for agro economic traits studied. Among all the studied populations, fresh herb-based essential oil content ranged from 0.1 % to 0.3 %, with a grand mean of 1.67 %. However, the estimated oil yield ranged from 44.4 kg/h to 120.73 kg/h with an average of 71.34 kg/h. Among the eleven phytochemical constituents detected in different concentrations in the essential oil of experimental sets, 4aα,7α,7aα-Nepetalactone (67.9-87.5 %) constituted the significant proportion of essential oil. Altogether, based on mean comparison, the population NC8 was found to be promising for estimated oil yield and 4aα,7α,7aα-Nepetalactone content. The greater heritability estimates (h2 bs) and genetic advance as percent of mean (GAM) were observed for important economic parameters, i. e., oil content, herb yield, and oil yield. The cluster analysis revealed the least interactions between various agro economic and phytochemical variables. The microscopic study of trichome showed a positive correlation of abaxial leaf surface with essential oil content. The promising antimicrobial potential of catmint oil was also observed against human health-related pathogens. The results infer from our study provide valuable insight for genetic improvement and product development in the catmint germplasm.

Factors associated with failed epidural blood patch after accidental dural puncture in obstetrics: a prospective, multicentre, international cohort study.

BACKGROUND: Epidural blood patch is commonly used for management of post-dural puncture headache after accidental dural puncture. The primary aim was to determine factors associated with failed epidural blood patch. METHODS: In this prospective, multicentre, international cohort study, parturients ≥18 yr receiving an epidural blood patch for treatment of post-dural puncture headache were included. Failed epidural blood patch was defined as headache intensity numeric rating scale (NRS) score ≥7 in the upright position at 4, 24, or 48 h, or the need for a second epidural blood patch, and complete success by NRS=0 at 0-48 h after epidural blood patch. All others were considered partial success. Multinominal logistic regression was used for statistical analyses with P<0.01 considered statistically significant. RESULTS: In all, 643 women received an epidural blood patch. Complete data to classify failure were available in 591 (91.9%) women. Failed epidural blood patch occurred in 167 (28.3%) patients; 195 (33.0%) were completely successful and 229 (38.7%) partially successful. A total of 126 women (19.8%) received a second epidural blood patch. A statistically significant association with failure was observed in patients with a history of migraine, when the accidental dural puncture occurred between lumbar levels L1/L3 compared with L3/L5 and when epidural blood patch was performed <48 h compared with ≥48 h after accidental dural puncture. In patients having radiological investigations, three intracranial bleeds were diagnosed. CONCLUSIONS: Failed epidural blood patch occurred in 28.3% of women. Independent modifiable factors associated with failure were higher lumbar level of accidental dural puncture and short interval between accidental dural puncture and epidural blood patch. A history of migraine was associated with a higher risk of second epidural blood patch. CLINICAL TRIAL REGISTRATION: NCT02362828.

Postoperative complications and myocardial injury in patients receiving air or oxygen. Prospective, randomised and pilot study.

BACKGROUND: Supplementary oxygen is administered during anaesthesia to increase oxygen delivery and prevent hypoxia. Recent studies have questioned this routine. In this pilot study, our main aim was to investigate if 21% oxygen compared to ≥50% reduces the risk of postoperative complications and myocardial injury. METHODS: In this pragmatic, multicentre, single-blind study, patients undergoing vascular surgery were randomised to receive a fraction of inspired oxygen (Fi O2 ) ≥ 0.50 and oxygen saturation determined by pulse oximetry (SpO2 ) ≥ 98% (group H) or Fi O2 of 0.21 and SpO2 > 90% (group N) oxygen perioperatively. The primary outcome was a composite outcome of major pre-defined postoperative complications assessed at 30 days. Myocardial injury was determined by serial troponin measurements. Data were analysed using generalised estimating equation, Mann-Whitney U test or chi-squared test, as appropriate. RESULTS: The 191 patients were randomised, and per-protocol principle was used for analyses. At 30-day follow-up, 43 out of 94 patients (46%) had a postoperative complication in group H and 36 out of 90 patients (40%) in group N, p = .46. New myocardial injury was seen in 27% versus 22% in Groups H and N respectively (p = .41). No differences in other outcomes were observed between the groups. Twelve patients (13%) in Group N had SpO2 < 90%, six recovered spontaneously and six required supplemental oxygen. At 1-year follow-up, one patient in group H had died. CONCLUSION: In this pilot study, postoperative complications were similar between the groups in patients randomised to Fi O2 of 0.21 or ≥0.50 and no difference was found in the incidence of new myocardial injury. Larger, prospective adequately powered studies are needed.

Peripheral Nerve Blocks Outperform General Anesthesia for Pain Control in Arthroscopic Rotator Cuff Repair: A Systematic Review and Meta-analysis.

PURPOSE: The purpose of this review is to compare the effectiveness of different peripheral nerve blocks and general anesthesia (GA) in controlling postoperative pain after arthroscopic rotator cuff repair (ARCR). METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review was conducted for the period of January 1, 2005, to February 16, 2021, by searching the following databases: PubMed, Cochrane, Embase, and Arthroscopyjournal.org. The primary outcomes of interest included 1-hour, 24-hour, and 48-hour pain scores on a numeric rating scale or visual analog scale (VAS). Inclusion criteria were English language studies reporting on adults (≥18 years) undergoing ARCR with peripheral nerve blockade. To synthesize subjective pain score data at each evaluation time point across studies, we performed random-effects network meta-regression analyses accounting for baseline pain score as a covariate. RESULTS: A total of 14 randomized controlled trials with 851 patients were included in the meta-analysis. Data from six different nerve block interventions, single-shot interscalene brachial plexus nerve block (s-ISB; 37.8% [322/851]), single-shot suprascapular nerve block (s-SSNB; 9.9% [84/851]), continuous ISB (c-ISB; 17.5% [149/851]), continuous SSNB (c-SSNB; 6.9% [59/851]), s-ISB combined with SSNB (s-ISB+SSNB; 5.8% [49/851]), s-SSNB combined with axillary nerve block (s-SSNB+ANB; 4.8% [41/851]), as well as GA (17.3% [147/851]) were included. Our meta-analysis demonstrated that c-ISB block had a significant reduction in pain score relative to GA at 1-hour postoperation (mean difference [MD]: -1.8; 95% credible interval [CrI] = -3.4, -.08). There were no significant differences in VAS pain scores relative to GA at 24 and 48 hours postoperatively. However, s-ISB+SSNB had a significant reduction in 48-hour pain score compared to s-ISB (MD = -1.07; 95% CrI = -1.92, -.22). CONCLUSIONS: It remains unclear which peripheral nerve block strategy is optimal for ARCR. However, peripheral nerve blocks are highly effective at attenuating postoperative ARCR pain and should be more widely considered as an alternative over general anesthesia alone. LEVEL OF EVIDENCE: Level II Systematic review and meta-analysis of Level I and II studies.

A Randomized, Placebo-Controlled Study to Evaluate the Effect of Bio-Enhanced Turmeric Formulation on Radiation-Induced Oral Mucositis.

INTRODUCTION: Oral mucositis is the most common toxicity of chemoradiotherapy treatment of head and neck cancers. The present study was performed to evaluate the effect of a researched turmeric formulation on oral mucositis in patients receiving chemoradiotherapy for oral cancer. METHODS: This randomized double-blinded placebo-controlled trial included 60 patients with oral cancer who had undergone radical surgery. Patients were equally randomized into 3 arms. Bio-enhanced turmeric formulation (BTF) capsules (low dose [1 g/day] or high dose [1.5 g/day]) or placebo was administered daily for 6 weeks with concurrent chemoradiotherapy. Study endpoints included the impact of the treatment on chemoradiotherapy-induced oral mucositis along with dysphagia, oral pain, dermatitis, and weight loss. RESULTS: The incidence of grade 3 toxicity of oral mucositis, oral pain, dysphagia, and dermatitis was significantly lower in patients who received BTF than placebo. Twenty-five and 20% patients in BTF 1 g/day (p = 0.011) and 1.5 g/day (p = 0.004) arms, respectively, developed grade 3 oral mucositis compared to 65% patients in the placebo arm. Thirty-five and 30% patients in BTF 1 g/day (p = 0.027) and 1.5 g/day (p = 0.011) arms, respectively, developed grade 3 oral pain compared to 70% patients in the placebo arm. Twenty-five and 20% patients in BTF 1 g/day (p = 0.025) and 1.5 g/day (p = 0.010) arms, respectively, developed grade 3 dysphagia compared to 60% patients in the placebo arm. Ten and 5% patients in BTF 1 g/day (p = 0.114) and 1.5 g/day (p = 0.037) arms. respectively, developed grade 3 dermatitis compared to 30% patients in the placebo arm. Patients under BTF supplementation experienced significantly less weight loss and greater compliance with treatment than placebo. CONCLUSION: BTF (BCM-95®) can significantly reduce chemoradiotherapy-induced severe oral mucositis, dysphagia, oral pain, and dermatitis in oral cancer patients. TRIAL REGISTRATION: Clinical Trials Registry, India (Registration No. CTRI) (CTRI/2015/12/006413 dated December 4, 2015).

Urban Warming of the Two Most Populated Cities in the Canadian Province of Alberta, and Its Influencing Factors.

Continuous urban expansion transforms the natural land cover into impervious surfaces across the world. It increases the city's thermal intensity that impacts the local climate, thus, warming the urban environment. Surface urban heat island (SUHI) is an indicator of quantifying such local urban warming. In this study, we quantified SUHI for the two most populated cities in Alberta, Canada, i.e., the city of Calgary and the city of Edmonton. We used the moderate resolution imaging spectroradiometer (MODIS) acquired land surface temperature (LST) to estimate the day and nighttime SUHI and its trends during 2001-2020. We also performed a correlation analysis between SUHI and selected seven influencing factors, such as urban expansion, population, precipitation, and four large-scale atmospheric oscillations, i.e., Sea Surface Temperature (SST), Pacific North America (PNA), Pacific Decadal Oscillation (PDO), and Arctic Oscillation (AO). Our results indicated a continuous increase in the annual day and nighttime SUHI values from 2001 to 2020 in both cities, with a higher magnitude found for Calgary. Moreover, the highest value of daytime SUHI was observed in July for both cities. While significant warming trends of SUHI were noticed in the annual daytime for the cities, only Calgary showed it in the annual nighttime. The monthly significant warming trends of SUHI showed an increasing pattern during daytime in June, July, August, and September in Calgary, and March and September in Edmonton. Here, only Calgary showed the nighttime significant warming trends in March, May, and August. Further, our correlation analysis indicated that population and built-up expansion were the main factors that influenced the SUHI in the cities during the study period. Moreover, SST indicated an acceptable relationship with SUHI in Edmonton only, while PDO, PNA, and AO did not show any relation in either of the two cities. We conclude that population, built-up size, and landscape pattern could better explain the variations of the SUHI intensity and trends. These findings may help to develop the adaptation and mitigating strategies in fighting the impact of SUHI and ensure a sustainable city environment.

Effect of Sotrovimab on Hospitalization or Death Among High-risk Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: Older patients and those with comorbidities who are infected with SARS-CoV-2 may be at increased risk of hospitalization and death. Sotrovimab is a neutralizing antibody for the treatment of high-risk patients to prevent COVID-19 progression. Objective: To evaluate the efficacy and adverse events of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease. Design, Setting, and Participants: Randomized clinical trial including 1057 nonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for progression conducted at 57 sites in Brazil, Canada, Peru, Spain, and the US from August 27, 2020, through March 11, 2021; follow-up data were collected through April 8, 2021. Interventions: Patients were randomized (1:1) to an intravenous infusion with 500 mg of sotrovimab (n = 528) or placebo (n = 529). Main Outcomes and Measures: The primary outcome was the proportion of patients with COVID-19 progression through day 29 (all-cause hospitalization lasting >24 hours for acute illness management or death); 5 secondary outcomes were tested in hierarchal order, including a composite of all-cause emergency department (ED) visit, hospitalization of any duration for acute illness management, or death through day 29 and progression to severe or critical respiratory COVID-19 requiring supplemental oxygen or mechanical ventilation. Results: Enrollment was stopped early for efficacy at the prespecified interim analysis. Among 1057 patients randomized (median age, 53 years [IQR, 42-62], 20% were ≥65 years of age, and 65% Latinx), the median duration of follow-up was 103 days for sotrovimab and 102 days for placebo. All-cause hospitalization lasting longer than 24 hours or death was significantly reduced with sotrovimab (6/528 [1%]) vs placebo (30/529 [6%]) (adjusted relative risk [RR], 0.21 [95% CI, 0.09 to 0.50]; absolute difference, -4.53% [95% CI, -6.70% to -2.37%]; P < .001). Four of the 5 secondary outcomes were statistically significant in favor of sotrovimab, including reduced ED visit, hospitalization, or death (13/528 [2%] for sotrovimab vs 39/529 [7%] for placebo; adjusted RR, 0.34 [95% CI, 0.19 to 0.63]; absolute difference, -4.91% [95% CI, -7.50% to -2.32%]; P < .001) and progression to severe or critical respiratory COVID-19 (7/528 [1%] for sotrovimab vs 28/529 [5%] for placebo; adjusted RR, 0.26 [95% CI, 0.12 to 0.59]; absolute difference, -3.97% [95% CI, -6.11% to -1.82%]; P = .002). Adverse events were infrequent and similar between treatment groups (22% for sotrovimab vs 23% for placebo); the most common events were diarrhea with sotrovimab (n = 8; 2%) and COVID-19 pneumonia with placebo (n = 22; 4%). Conclusions and Relevance: Among nonhospitalized patients with mild to moderate COVID-19 and at risk of disease progression, a single intravenous dose of sotrovimab, compared with placebo, significantly reduced the risk of a composite end point of all-cause hospitalization or death through day 29. The findings support sotrovimab as a treatment option for nonhospitalized, high-risk patients with mild to moderate COVID-19, although efficacy against SARS-CoV-2 variants that have emerged since the study was completed is unknown. Trial Registration: ClinicalTrials.gov Identifier: NCT04545060.

Trends for in-office usage of pharmacological sedation agents in India: A narrative review.

Background and Aims: Conscious sedation plays a significant role in in-office pharmacological behavior management for short-term procedures in children and apprehensive adults. The advantage conscious sedation provides is by improving quality of care provided by decreasing pain and anxiety while maintaining a patent airway and adequate spontaneous ventilation. Methodology: Present review was conducted to evaluate recent trends regarding use of in-office pharmacological sedation agents in India. A rigorous search was conducted through five electronic databases namely PubMed, Scopus, Web of Science, Cochrane Database, and CTRI (Clinical Trial Registry - India). The search period was defined to be last 5 years, that is, from 1st January 2014 to 31st July 2019. Terminologies "Conscious Sedation," "In-office Sedation," "Midazolam," "Nitrous Oxide," "India" were included in the search. The Boolean Operation "OR" and "AND" were applied to combine the terminologies. Results: A total of 20 studies were identified following strict inclusion and exclusion criteria. The included studies were evaluated for study design, speciality involved, number of individuals and their age groups, drugs compared along with route and dosage, procedures undertaken, place of study and results. Dental fraternity (13) had more number of trials conducted as compared to medical fraternity (7) in the stimulated period, with South Indian region having maximum trials registered or published. Conclusion: Midazolam was observed to the drug of choice for in-office sedation procedures in Indian Scenario. The limitation of study is that the published clinical studies are limited to a few states of India.